Background: The development of fulminant Clostridium difficile colitis (FCDC) requires prompt operative intervention and is associated with a high mortality rate. The aim of this study was to use a case-control design to define the clinical and laboratory parameters that predict which patients with Clostridium difficile infection are most likely to progress to FCDC. Methods: Cases from 1994 to 2006 with documented in-hospital progression of Clostridium difficile infection to FCDC were matched retrospectively at the start of medical therapy by age, sex, and intensive care unit (ICU) status to controls with Clostridium difficile infection who did not develop FCDC. Chi-Square and multivariable logistic regression were used to identify risk factors for progression to FCDC. Results: A total of 35 patients with FCDC were matched to 70 controls with Clostridium difficile infection who did not develop FCDC. The patients with FCDC underwent colectomy after an average of 4.6 days of medical therapy and had a mortality rate of 40%. On multivariate analysis, independent risk factors for the development of FCDC were a WBC > 16,000 cells/mm3 (P < .01) at initiation of therapy, operative therapy within the last 30 days (P = .03), a history of inflammatory bowel disease (P = .04), and a history of intravenous immunoglobulin treatment (P < .01). Conclusions: Leukocytosis, recent prior operative therapy, and a history of inflammatory bowel disease and intravenous immunoglobulin treatment were negative prognostic indicators for patients with Clostridium difficile infection. The presence of these factors merits close observation for progression to FCDC and acceleration of the planning process for operative intervention.